As clearly shown for the Wnt signaling, the study of rare genetic disorders of the skeleton can yield insights that fuel novel therapeutic approaches for the treatment of both rare and common skeletal disorders. Our recent studies have linked Pyle's disease (OMIM-265900), a rare skeletal disease characterized by long bones with wide and expanded trabecular metaphyses, thin cortical bone, and bone fragility, to loss of function mutations in Secreted Frizzled Receptor Protein 4 (SFRP4), a Wnt inhibitor which functions as a decoy receptor for Wnt ligands. Pyle's disease patients present also with thin calvarium, smaller head circumference or abnormal shape and dental abnormalities such as delayed tooth eruption, cavities and malocclusion. We have studied a knockout mouse model to determine the role of Sfrp4 in the pathogenesis of Pyle's disease as well as in skeletal development and homeostasis and shown that in mice, Sfrp4 deletion causes skeletal deformities closely mimicking those seen in Pyle's disease: increased trabecular bone formation and cortical bone thinning due to decreased periosteal and endosteal apposition and increased endocortical resorption. Despite their clinical significance in determining the size, thickness and strength of cortical bone, the cellular characteristics of the periosteum and endosteum niches, as well as the local or paracrine regulatory factors, including Wnt ligands, that regulate their activity are relatively poorly understood. We have found that Sfrp4 is expressed in a newly identified population of periosteal progenitor cells in the long bones and calvarium, which are involved in cortical bone formation, suggesting that Sfrp4-mediated signaling may contribute to the expansion, differentiation and function of periosteal cells. On the endosteal surface, Sfrp4 is expressed by bone lining cells, osteoblasts and osteoclasts and impairs osteoclast differentiation and activity via non- canonical Wnt signals, supporting a local function of Sfrp4 in the endosteum. In the cortex, we found that osteocytes, which represent >90% of cells and are poised to communicate with cells on the bone surfaces, also express Sfrp4 and are affected by its deletion, suggesting that Sfrp4 might also affect the osteocytes and/or their role in the regulation of cortical homeostasis. We propose here to use innovative techniques and mouse genetics to explore the periosteum and endosteum biology and the way in which they communicate, possibly through the osteocytes. Our objective is to identify the role that Sfrp4-mediated signaling plays in regulating their activity. We propose three specific aims to test this hypothesis: Aim 1 will focus on the role of Sfrp4 in periosteal progenitor cells while Aim 2 will explore the role of Sfrp4 in remodeling along the endosteum and Aim 3 will determine Sfrp4 effect on osteocytes. Performing and translating findings from these studies into effective mechanisms will have broad significance for our understanding of the mechanism underlying cortical biology and will be translatable to human diseases associated with cortical bone fragility. !